Chemokines are a peptide of 8 to 10 kDa that plays an important role in migration and activation of leukocytes. Chemokines are classified into four subgroups, i.e. “C chemokines”, “CC chemokines”, “CXC chemokines” and “CX3C chemokines”, based on positions of the first two cysteines (C) among the four cysteines present at the N-terminus of chemokines. MCP-1, one of chemokines belonging to CC chemokines subfamily, is a monocyte chemotactic-activating factor with 76 amino acid residues that was cloned from human glioma cell line and monocytic leukemia cell line in 1989 (see e.g. Yoshimura, T. et al., “FEBS Letter”, 1989, Vol. 244, p. 487-493). MCP-1 is a multifunctional molecule that is produced by monocytes, vascular endothelial cells, and fibroblasts and acts on monocytes, T cells and basophiles to enhance their migrating activity, production and release of active oxygen and lysosome enzyme, production and induction of cytokines, degranulation of basophiles, induction of adhesive molecules expression, production and release of histamine and leukotrienes, etc.
With progress of analysis using disease model animals, especially for chronic inflammation, MCP-1 has been indicated to be responsible for some inflammatory diseases (see e.g. Schrier, D. J. et al., “Journal of Leukocyte Biology”, 1998, Vol. 63, p. 359-363). Besides, it has been reported that inhibition of MCP-1 activity in these disease model animals resulted in reduction of symptoms. For instance, it has been reported that administration of anti-MCP-1 antibody to collagen-induced arthritis (hereinafter also referred to as “CIA”) model or adjuvant-induced arthritis model of rats provides preventive and treating effects for arthritis to alleviate arthritic symptoms (see e.g. Youssef, S. et al., “Journal of Clinical Investigation”, 2000, Vol. 106, p. 361-371; and Ogata, H. et al., “Journal of Pathology”, 1997, Vol. 182, p. 106-114). It has also been reported that, in case of MRL-lpr mice where arthritis spontaneously occurs and lasts throughout the life, arthritis aggravates when MCP-1 is administered but is reduced when antagonist to MCP-1 is administered (see e.g. Gong, J. H. et al., “Journal of Experimental Medicine”, 1997, Vol. 186, p. 131-137).
Moreover, with progress of analysis using mice with deficiency in genes of MCP-1 and its receptor CCR2, it has been indicated that in some inflammatory diseases MCP-1/CCR2 is essential for macrophage invasion involved in onset of disease. For instance, it has been reported that MCP-1 deficiency in autoimmune mice inhibited migration of macrophages and T cells to protect the kidney, the lung and skin, resulting in prolonging of life, and that macrophage invasion to inflammation experimentally induced in the abdomen was inhibited in knockout mice with disrupted CCR2 gene (see e.g. Kurihara, T. et al., “Journal of Experimental Medicine”, 1997, Vol. 186, p. 1757-1762). There is also a report that deficiency in MCP-1 or CCR2 in arteriosclerosis model mice inhibited macrophage migration on the artery wall and formation of sclerotic focus (see e.g. Gosling, J. et al., “Journal of Clinical Investigation”, 1999, Vol. 103, p. 773-778; and Boring L. et al., “Nature”, 1998, Vol. 394, p. 894-897).
In relation to human diseases, higher MCP-1 level in synovial fluid in rheumatoid arthritis (hereinafter also referred to as “RA”) patients was found as compared to that of osteoarthritis patients, implying that MCP-1 may play a major role in induction/enhancement of inflammatory cell invasion and inflammation (see e.g. Akahoshi, T. et al. “Arthritis and Rheumatism”, 1993, Vol. 36, p. 762-771; and Koch, A E. et al., “Journal of Clinical Investigation”, 1992, Vol. 90, p. 772-779). Epidemiological investigation also revealed that MCP-1 may be involved in onset of myocardial infarction and arteriosclerosis and an activity to inhibit the cell migration mediated by MCP-1 can be a risk factor of these diseases. It is thus expected that an anti-MCP-1 antibody may be used for inhibiting a cell migration mediated by MCP-1 to thereby prevent and treat myocardial infarction and arteriosclerosis.
As described above, it has been revealed that MCP-1 is involved in invasion of inflammatory cells and induction of inflammation in chronic inflammatory diseases and arteriosclerosis. It is thus expected that development of a specific monoclonal antibody that neutralizes the biological activity of MCP-1 would provide a clinical means for effectively treating diseases where macrophage invasion is a main factor. Several monoclonal antibodies binding to MCP-1 have already been obtained from mice and rats and were reported to inhibit macrophage invasion in rat Masugi type nephritis and to inhibit macrophage invasion, increase in right ventricular pressure and hypertrophy of the inner membrane of pulmonary arteriole in rat pulmonary hypertension model (see e.g. Wada, T. et al., “FASEB Journal”, 1996, Vol. 10, p. 1418-1425; and Kimura, H. et al., “Lab. Invest.”, 1998, Vol. 78, p. 571-581).